In humans, mutations in the cellular Ras gene (c-ras) which render Ras constitutively active, have been associated with different types of cancers (Bos et al., Cancer Res. 94:4682-4689). Ras relays signals from receptor tyrosine kinases, (Fantl et al., 1993, Annu. Rev. Biochem., 62:453-481), non-tyrosine kinase receptors (Woodrow et al., 1993, J. Immunol., 150: 3853-3861) and heterotrimeric G protein-coupled receptors (Van Corven et al., 1993, Proc. Nat'l . Acad. Sci., 90:1257-1261). Ras is located at the inner surface of the plasma membrane. Activation of cell surface receptors promotes the exchange of Ras-bound GDP for GTP, thereby causing a conformational change in Ras. This conformational change activates Ras so that it interacts with downstream targets or effectors (Wittinghofer et al., 1996, Trends In Biochem. Sci., 21:488-491.
Several candidate Ras effectors have been proposed based on their ability to bind to Ras through its effector loop. Among these are: Raf, PI-3 kinase, members of the Ral-GDS family, Rin-1, AF-6, diacylglycerol kinases, PKC .zeta., and MEKKl (See, e.g., Katz et al., 1997, Curr. Opin. Genet. Dev., 7:75-79; Marshall, 1996, Curr. Opin. Cell Biol., 8:197-204). Activation of effectors such as these leads to activation of other downstream signal transduction molecules. This signaling cascade culminates in the modulation of gene expression, and thereby causes changes in cellular function, growth, and division.